GLB1-related disorders: GM1 gangliosidosis and Morquio B disease

Abstract

GLB1-related disorders comprise two phenotypically unique disorders: GM1 gangliosidosis and Morquio B disease. These autosomal recessive disorders are caused by b-galactosidase deficiency. A hallmark of GM1 gangliosidosis is central nervous system degeneration where ganglioside synthesis is highest. The accumulation of keratan sulfate is the suspected cause of the bone findings in Morquio B disease. GM1 gangliosidosis is clinically characterized by a neurodegenerative disorder associated with dysostosis multiplex, while Morquio B disease is characterized by severe skeletal manifestations and the preservation of intelligence. Morquio B disease and GM1 gangliosidosis may be on a continuum of skeletal involvement. There is currently no effective treatment for GLB1-related disorders. Recently, multiple interventions have been developed and there are several ongoing clinical trials.

Therapeutic developments for neurodegenerative GM1 gangliosidosis

“…Beyond nanotechnology-mediated ERT, β-gal fusion proteins have demonstrated preclinical promise. Condori et al fused β-gal with plant lectin ricin toxin B-subunit (RTB), which binds cell-surface glycolipids/proteins that contain galactose/galactosamine (Cho and Jin, 2021), leading to a reduction of GM1 ganglioside levels in GM1-patient fibroblasts (Condori et al, 2016). IV injections of β-gal: RTB in GM1-affected mice led to moderate increases in neural β-gal activity (<10% normal) compared to untreated controls (Weesner et al, 2022).…”

“…Lysosomal accumulation increases throughout disease, with an increasing number of swollen lysosomes leading to neural cell death, although the mechanism of neurodegeneration is incompletely understood. Reviews looking at the pathophysiology of GM1 exist elsewhere (Brunetti-Pierri and Scaglia, 2008;Cho and Jin, 2021;Nicoli et al, 2021;Rha et al, 2021;Senarathne et al, 2023). Current treatment methods focus on restoring endogenous β-gal activity and/or clearing accumulated GM1 gangliosides to decrease the disease burden.…”

Validation of a highly sensitive HaloTag-based assay to evaluate the potency of a novel class of allosteric β-Galactosidase correctors

“…Mutations in the polypeptide’s sequence substantially reduce the folding efficiency and may result in loss-of-function phenotypes or related diseases [ 4 ]. Autosomal recessive mutations in the galactosidase beta 1 ( GLB1 ) gene encoding the lysosomal hydrolase β-galactosidase (β-Gal) manifest in phenotypically distinct GLB1-related lysosomal storage disorders (LSD) [ 5 , 6 ]. For example, the p.Ile51Thr mutation is common among adult Japanese patients affected with late-onset GM1-gangliosidosis [ 7 ], p.Arg59His causes severe infantile GM1-gangliosidosis with cardiac involvement [ 8 , 9 ], p.Arg201Cys is associated with late infantile/juvenile type 2 GM1-gangliosidosis [ 10 , 11 ], and p.Trp273Leu has been linked with juvenile Morquio B disease [ 12 ].…”